The use in medicine of a high number of these complexes is widely reported, for instance as stabilizers for the pharmaceutical preparations or as antidotes in case of ingestion of toxic metal species.
Physiologically tolerable complexes formed by chelating agents and bi- or trivalent metal ions are used as diagnostic agents in imaging techniques such as X-ray, nuclear magnetic resonance (NMR) and scintigraphy.
In particular, magnetic resonance imaging (MRI) is a renowned, powerful diagnostic procedure used in medical practice (see Stark, D. D., Bradley, W. G., Jr., Eds. "Magnetic Resonance Imaging" The C. V. Mosby Company, St. Louis, Mo. (USA), 1988) which relies on the use of paramagnetic pharmaceutical compositions, preferably containing chelated complexes of bi- or trivalent paramagnetic metal ions, usually belonging to the class of transition metals, or rare earth, with polyaminocarboxylic acids and/or their derivatives or analogues.
The images (basically coming from the NMR signal of water protons) are the result of a complex interaction of different parameters, such as proton density and T.sub.1 and T.sub.2 relaxation times. A contrast enhancement can be obtained through the administration of exogenous chemical substances which significantly change the resonance properties of the nearby water protons (see Lauffer, R. B. Chem. Rev. 1987,87,901). Due to the high capacity of gadolinium complexes of reducing the relaxation times of hydrogen nuclei of nearby water molecules through dipolar interaction, scientists have investigated, patented and published a lot of works on these complexes. Some of such complexes have been approved as MRI contrast media (Gd-DTPA/Dimeg, N-methylglucamine salt of gadolinium diethylenetriaminepentaacetic acid, MAGNEVIST.RTM., Schering; Gd-DOTA/Dimeg, N-methylglucamine salt of gadolinium 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetracetic acid, DOTARED.RTM., Guerbet; HPDO3A, gadolinium 10-(2-hydroxypropyl)-1,4,7,10-tetraazacycl-ododecan-1,4,7-triacetic acid, PROHANCD.RTM., Bracco; Gd-DTPA-BMA, Gd-DTPA bismethylamide, OMNISCAN.RTM., Salutar).
A list of significant patent documents showing the state of the art in this diagnostic field, even though uncompleted, is represented by: EP 71564 (Schering), U.S. Pat. No. 4,639,365 (Sherry), U.S. Pat. No. 4,615,879 (Runge), DE-A-3401052 (Schering), EP 130934 (Schering), EP 65728 (Nycomed), EP 230893 (Bracco), U.S. Pat. No. 4,826,673 (Mallinckrodt), U.S. Pat. No. 4,639,365 (Sherry), EP 299795 ( Nycomed ), EP 258616 (Salutar), WO 8905802 (Bracco).
The selection of the suitable compound is based on the evaluation of different parameters such as relaxivity, toxicity, distribution in the human body, excretion and so on. Three important properties are mainly needed to use a complex of Gd.sup.(3+) as a potential MRI contrast agent. First, a high thermodynamic (and possibly kinetic) stability of the complex, i.e. a low tendency to release free Gd.sup.(3+) ions, per se highly toxic in vivo. Second, the presence of at least one water molecule directly coordinated to the metal in the inner coordination sphere and able to rapidly exchange with the bulk one. Third, a high water solubility (.gtoreq.0.5 mol/L). Although Gd-DTPA and Gd-DOTA are stable and water-soluble gadolinium chelates, they are ionic compounds (i.e. formally charged, namely -2 for Gd-DTPA and -1 for Gd-DOTA) which are made neutral with the formation of N-methylglucamine salts. Therefore the solutions contain charged particles, which affect their osmolality characteristics. Injectable concentrated solutions (0.5-1.0M) of such salts are much more hyperosmolal compared to blood and physiological fluids. Hyperosmolality can produce, in vivo, oedemas and other undesired side effects.
As a consequence, several attempts have been made to develop novel non-ionic metal complexes, which overcome or limit the above mentioned drawbacks. A solution was proposed by Tweedle M. F. et al. in patent U.S. Pat. No. 4,885,363 which deals with the preparation of gadolinium complex with 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclodo-decan-1, 4,7-triacetic acid (HP-DO3A, PROHANCE.sup.R, Bracco) in which one of the carboxylic groups has been removed to make the gadolinium complex neutral. Another way is represented by the conversion of one or more free carboxylic groups in the molecule of the complexing agent, into non-ionizable, neutral groups. For example, S. C. Quay, in U.S. Pat. Nos. 4,687,658 and 4,687,659 describes ester and amido derivatives of DTPA complexes (Gd-DTPA-bismethylamide, Gd-DTPA-BMA, gadodiamide, OMNISCA.RTM., Salutar, was found particularly remarkable). In the same way, Dean et al., in U.S. Pat No. 4,826,673 disclose mono- and polyhydroxyalkylamido DTPA derivatives and their use as complexing agents for paramagnetic ions. Patent applications DE 3324235-A and DE 3324236-A deal with mono- and polyhydroxyalkylamido DTPA derivatives and their use as complexing agents of paramagnetic ions. Also Australian patent application 78995/87 claims amido complexing agents used for MRI and X-ray procedures.